This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We recently completed a double-blind placebo-controlled human laboratory study demonstrating that treatment with a low dose of the acetylcholinesterase (AChE) inhibitor rivastigmine reduced methamphetamine (MA)-induced craving (see Preliminary Studies, Fig. 2). This finding is consistent with the preclinical report indicating that the AChE inhibitor donepezil reduced MA-seeking behavior in rats following exposure to a non-contingent dose of MA (Hiranita et al. 2006). To extend our clinical findings, we propose a 3-year human laboratory study to evaluate effects of higher doses of rivastigmine on MA-induced craving and on self-administration of MA. Our recently completed work indicates that 3mg rivastigmine attenuated MA-induced craving in the laboratory. Given that higher dosages of this produce greater inhibition of nicotinic acetylcholine (ACh) receptors (in the treatment of Alzheimer s disease), it is reasonable to predict that 6mg and 12mg will have more pronounced effects on craving and other measures of reinforcement. This human laboratory study is a critical next step in the evaluation of rivastigmine as a potential treatment for MA dependence. We propose to include only participants exhibiting MA-induced craving by screening potential participants prior to admission (criterion based upon Preliminary Studies, Fig. 5). Selection of participants demonstrating MA-induced craving will facilitate assessment of effects of rivastigmine on craving. Primary Objective:To characterize the effects of treatment with rivastigmine (0, 3, and 6 mg) on craving produced by experimental administration of METH (0, 15 and 30mg, IV). Secondary Objective:To characterize the effects of treatment with rivastigmine (0, 3, and 6 mg) on choices for METH exhibited in a self-administration paradigm. Novel Medication Development Strategies for MA Dependence Are Needed More people worldwide use amphetamine-type stimulants than any illicit drug besides cannabis, and MA abuse and dependence is the fastest growing drug problem in the United States. Our research group has recently completed safety and preliminary efficacy trials of potential medications for treating MA dependence using selegiline (Newton et al. 2005a), bupropion (Newton et al. 2005d;2006), aripiprazole (data presented at SFN 2005), and perindopril (data presented at CPDD 2006). Despite these efforts, much work remains in identifying an effective pharmacotherapy for MA dependence. The neurobiological actions by MA unquestionably involve dopamine (DA), serotonin, and norepinepherine, but also include alterations to cholinergic neurotransmitter systems. Candidate compounds that target ACh are attractive options for development that have not received adequate attention.